Machado J C, Oliveira C, Carvalho R, Soares P, Berx G, Caldas C, Seruca R, Carneiro F, Sobrinho-Simöes M
IPATIMUP, 4200 Porto, Portugal.
Oncogene. 2001 Mar 22;20(12):1525-8. doi: 10.1038/sj.onc.1204234.
In diffuse gastric carcinoma, despite common E-cadherin gene (CDH1) mutations, tumors show absence of CDH1 loss of heterozigosity (LOH) in most cases. This observation challenges the classical two-hit model of tumor suppressor gene inactivation. In order to investigate whether or not CDH1 promoter methylation may function as the second hit we analysed a series of 23 sporadic gastric carcinomas for the presence of CDH1 mutations, CDH1 promoter methylation, LOH and E-cadherin expression. CDH1 mutations were detected in nine of the 16 (56.3%) diffuse gastric carcinomas and in none of the seven intestinal gastric carcinomas. In diffuse gastric carcinomas harboring CDH1 mutations, LOH was observed in a single case. Loss of plasma membrane E-cadherin expression was consistently found in all nine cases with CDH1 mutation, suggesting that tumors inactivated the remaining CDH1 allele via a different mechanism. CDH1 promoter methylation was observed in nine of the 16 (56.3%) diffuse-type gastric carcinoma cases, including six of the nine cases (66.7%) harboring CDH1 mutations. CDH1 promoter methylation was also seen in two (28.6%) intestinal-type cases. Our results show that CDH1 promoter methylation is the second hit in more than half of the sporadic diffuse gastric carcinoma cases harboring CDH1 mutations.
在弥漫性胃癌中，尽管常见E-钙黏蛋白基因（CDH1）发生突变，但在大多数情况下，肿瘤显示不存在CDH1杂合性缺失（LOH）。这一观察结果对肿瘤抑制基因失活的经典双打击模型提出了挑战。为了研究CDH1启动子甲基化是否可能作为第二次打击，我们分析了一系列23例散发性胃癌，检测其CDH1突变、CDH1启动子甲基化、LOH和E-钙黏蛋白表达情况。在16例弥漫性胃癌中有9例（56.3%）检测到CDH1突变，而7例肠型胃癌中均未检测到。在携带CDH1突变的弥漫性胃癌中，仅1例观察到LOH。在所有9例CDH1突变病例中均一致发现质膜E-钙黏蛋白表达缺失，这表明肿瘤通过不同机制使剩余的CDH1等位基因失活。在16例弥漫型胃癌病例中有9例（56.3%）观察到CDH1启动子甲基化，其中包括9例携带CDH1突变病例中的6例（66.7%）。在2例（28.6%）肠型病例中也观察到CDH1启动子甲基化。我们的结果表明，在超过一半携带CDH1突变的散发性弥漫性胃癌病例中，CDH1启动子甲基化是第二次打击。
